CN104288772A - Combined application of cholinesterase inhibitor and muscarinic receptor blocker - Google Patents
Combined application of cholinesterase inhibitor and muscarinic receptor blocker Download PDFInfo
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- CN104288772A CN104288772A CN201410461187.5A CN201410461187A CN104288772A CN 104288772 A CN104288772 A CN 104288772A CN 201410461187 A CN201410461187 A CN 201410461187A CN 104288772 A CN104288772 A CN 104288772A
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- cholinesterase inhibitor
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Abstract
Combined application of a cholinesterase inhibitor and a muscarinic receptor blocker is applied to preparation of a medicine for promoting liver regeneration after hepatectomy. After hepatectomy, the combination of the cholinesterase inhibitor and the muscarinic receptor blocker has obvious effects of promoting liver regeneration, minimizing swelling in hepatic lobule and reducing number of hepatic cells of vacuolar degeneration. Furthermore, recovery of liver function is promoted. In addition, the combination has no obvious toxic or side effect.
Description
Technical field
The present invention relates to cholinesterase inhibitor and muscarinic acceptor blocker and combine purposes for the preparation of promoting in the medicine of liver regeneration.
Background technology
Easily there is the complication such as hepatocellular damage, microhepatia syndrome, liver failure in complicated hepatectomy on a large scale etc., can cause death time serious.These complication are higher with incidence rate in the patient of obstructive jaundice and liver cirrhosis in the preoperative.
Liver cell regeneration can compensate the hepatocyte that excision and liver tissue injury cause and reduce, and recovers the physiological function of liver, has very important effect to control microhepatia syndrome, liver failure etc.
Cholinesterase inhibitor is that a class can combine with acetylcholine esterase (ChE), and suppress the medicine of cholinesterase activity, its effect is that the Ach that cholinergic nerve endings is discharged piles up, and performance M sample and the effect of N sample strengthen and play the effect of excited cholinoceptor.
Muscarinic receptor blocker can block the muscarinic receptor after joint on the effector cell arranged of cholinergic nerve, has lax visceral smooth muscle, removes smooth muscle spasm, suppresses the secretion of salivary gland, sweat gland, gastrointestinal gland etc., removes vagus nerve and scrape the about effect such as flesh, excited respiratory center to the suppression of heart, lax iris.
Patent documentation CN102580099A reports muscarinic acceptor blocker and the cholinesterase inhibitor purposes for anti-hepatic ischemia-reperfusion injury.
Up to now, the report of liver regeneration is not promoted about muscarinic acceptor blocker and cholinesterase inhibitor coupling.
Summary of the invention
The present inventor finds, cholinesterase inhibitor and muscarinic acceptor blocker use in conjunction can promote the regeneration of liver, particularly on a large scale, Hepatectomy can promote the regeneration of liver, alleviate the hepatocyte quantity of swelling and vacuolar degeneration in lobules of liver, promote the recovery of liver function, and without obvious toxic-side effects.
Given this, the invention provides cholinesterase inhibitor and muscarinic acceptor blocker and combine purposes for the preparation of promoting in the medicine of liver regeneration, especially for the purposes being prepared in Hepatectomy and promoting in the medicine of liver regeneration.
The present invention and then provide cholinesterase inhibitor and muscarinic acceptor blocker to combine purposes in the medicine of the hepatic insufficiency caused because of hepatocyte lazy weight for the preparation for the treatment of or prevention, the purposes in the medicine of the hepatic insufficiency caused because of hepatocyte lazy weight especially for preparation treatment or prevention Hepatectomy.
The present invention and then provide cholinesterase inhibitor and muscarinic acceptor blocker to combine the purposes of the medicine for the preparation of prevention or treatment microhepatia syndrome, especially for the purposes of the medicine of preparation prevention or treatment Hepatectomy microhepatia syndrome.
Described cholinesterase inhibitor be preferably selected from neostigmine, Neostigmine, physostigmine, pyridostigmine, this bright, galantamine, edrophonium chloride, ambenonium chloride, demecarium bromide, tacrine of pyridinium bromide one or more.Be more preferably neostigmine.
Described muscarinic acceptor blocker be preferably selected from Anisodamine, scopolamine, atropine, melyltropeine, tropicamide or probanthine one or more.Be more preferably Anisodamine.
In purposes of the present invention, the part by weight of cholinesterase inhibitor and muscarinic acceptor blocker is preferably 1:50-800, is more preferably 1:200-600, most preferably is 1:500.
Medicine of the present invention can be the medicine of cholinesterase inhibitor and muscarinic acceptor blocker mixing, also can be the medicine of cholinesterase inhibitor and muscarinic acceptor blocker subpackage.
Medicine described in the present invention can be any suitable dosage form that cholinesterase inhibitor and muscarinic acceptor blocker and pharmaceutically acceptable carrier form.Such as, tablet, capsule, soft capsule, oral liquid, granule, suspending agent, pill, drop pill, intravenous fluid, subcutaneous injection liquid etc. can be enumerated.Preparation of the present invention can be slow releasing preparation.
Purposes of the present invention is when for human administration, and the dosage of cholinesterase inhibitor (preferred neostigmine) is 1.25 ~ 60 μ g/kg, is preferably 1.7-15 μ g/kg, is more preferably 4 μ g/kg.The dosage of muscarinic acceptor blocker (preferred Anisodamine) is 1mg-3mg/kg, is preferably 1.7mg-2.3mg/kg, is more preferably 2mg/kg.
Accompanying drawing explanation
Fig. 1 shows the liver regeneration rate of obstructive jaundice hepatectomy rat in treatment group and matched group.
Fig. 2 shows liver regeneration index testing result in treatment group and matched group.
Fig. 3 shows the hepatocyte Ki-67 expression of liver more than obstructive jaundice hepatectomy in treatment group and matched group.
Fig. 4 shows the testing result for the treatment of group and matched group ICG PDR.
Fig. 5 shows the pathology of hepar change of sham operated rats (Fig. 5 A), matched group (Fig. 5 B) and treatment group (Fig. 5 C) rat.
Fig. 6 is the hepatocyte Ki-67 expression showing liver more than obstructive jaundice hepatectomy in treatment group and matched group.
Fig. 7 shows the pathology of hepar change of sham operated rats, matched group and treatment group rat.
Detailed description of the invention
Laboratory animal and reagent
Male Wistar rat, body weight 240 ~ 260g, is provided by Military Medical Science Institute's Experimental Animal Center.
Experimental drug is methyl-sulfuric acid neostigmine injection (Xinyi, Shanghai Jin Zhu pharmaceutcal corporation, Ltd) and anisodamine (Tianjin KingYork Amino Acid Co., Ltd.).
The making of obstructive jaundice model
Preoperative 12 h fast of rat, can't help water.This operation method carries out under use surgical microscope and etherization.Anaesthetize successfully, rat dorsal position fixed, skin of abdomen iodophor disinfection, gets Median incision on upper abdomen, free common bile duct, cuts off, to prevent bile duct from leading to, then close abdomen again in the middle of after, the dual ligation of near-end far away with 5-0 silk thread.
Biliary drainage and partially hepatectomized
Bile duct ligation, after seven days, carries out second time abdominal under etherization.Biliary drainage is that the support made by sterile blood inner catheter tube (PVG gold ring medical treatment company limited, China, Shanghai) by inserting one section of 8 millimeters long reconnects near-end and far-end common bile duct, is suitably being fixed by support with purse string suture.Then reference literature method (Higgins GM, Anderson RM.Experimental pathology of liver resection.Arch Pathol.1931; 12:186-197) carry out 68% hepatectomy, the lobe of the liver being about to excision of existing side by side carries out weighing to calculate total liver weight.
Drug treating and sample collection
Two groups are divided at random: associating Anisodamine and neostigmine group (treatment group) and normal saline group (matched group), often group 6 rats after the obstructive jaundice rat of 1 week is carried out biliary drainage and partially hepatectomized.Anisodamine with 25mg/kg, neostigmine with 50 μ g/kg mixing pneumoretroperitoneum drug administration by injection.After hepatectomy, start administration immediately and continue two days, every day is administered twice.Control rats injection normal saline.Establish rats in sham-operated group 6 in addition.
After 48 hours, rat etherization is opened abdomen at second operation.Get residual regeneration lobe of the liver to weigh.Be fixed in 10% formalin-phosphate buffer (pH7.4), use for histopathological analysis.
Indocyanine green (ICG) excretion test
ICG (Dandong medical treatment company limited produces) is dissolved in sterile water for injection by 2.5mg/ml.First the ICG solution of fresh preparation is injected rat side femoral vein (2.5mg/kg) fast during mensuration, after injecting, carry out blood sampling from postcava, each 150-200 μ l when 1,3 and 5 minute, and add anticoagulant heparin.Get the bovine serum albumin of 50 μ L plasma samples and 950 μ L 1% weight/volume and the NaCl aqueous solution of 0.9% weight/volume after centrifugal, then carry out spectrophotometric colo in 805nm place.The slope of the semilog attenuation curve of the OD value of diluting plasma when PDR is 1,3 and 5 minute.
The assessment of liver regeneration
Employing two the independently Testing index of the assessment of liver regeneration: the regeneration of liver mass is to estimate when residual regeneration liver weight accounts for hepatectomy during sacrifice of animal that total liver percentage ratio heavily represents, and use following formulae discovery: liver regeneration (%)=A/B × 0.68 × 100, the wherein residual regeneration liver weight of A representative when putting to death animal, B represents the weight that hepatectomizes, and accounts for 68% of whole liver weight.The Ki-67 label index of assessment hepatocyte growth utilizes immunohistochemical method to measure: the hepatic tissue that formalin is fixing carries out paraffin embedding, makes 5 μm of thick sections, require to specifications to carry out immunohistochemical staining with the monoclonal antibody of little mouse-anti Ki-67 (BD Pharmingen company) after dewaxing rehydration, haematoxylin is redyed.Random selecting 10 high power fields (400 ×) under optical microscope, the hepatocyte number of the counting Ki-67 labelling positive accounts for the percentage ratio of hepatocyte sum as Ki-67 label index.
Morphologic detection
Liver tissues of rats specimen is after 10% formalin is fixing, and routine paraffin wax embeds, 5 μm of sections, and haematoxylin Yihong (HE) dyes.Om observation carries out the pathological analysis of hepar damnification, compares bile duct proliferation and hepatocyte injury situation.
Statistical analysis
All data acquisitions mean ± standard deviation represents.T-inspection is compared between being used for two groups.The comparison of more than 2 groups adopts one factor analysis of variance (ANOVA), utilizing SPSS17.0 to carry out statistical analysis, getting P<0.05 for there being statistical significance.
Experimental result
Use in conjunction Anisodamine and neostigmine can promote Hepatectomy liver regeneration
Biliary drainage and partially hepatectomized are carried out to the obstructive jaundice rat of 7 days, liver regeneration degree was assessed in postoperative 48 hours.Result shows that the liver regeneration rate of matched group and treatment group is respectively 57.7 ± 7.8% and 68.9 ± 4.3% (Fig. 1), and two group differences significantly (P<0.05).The testing result of hepatocyte Ki-67 label index shows, the liver cell proliferation situation for the treatment of group is significantly better than matched group (P<0.05) (Fig. 2, Fig. 3).These results show, Anisodamine/neostigmine therapeutic alliance can improve the liver regeneration of obstructive jaundice rats Hepatectomy.
ICG testing result shows that use in conjunction Anisodamine and neostigmine can promote Hepatectomy liver function recovery
ICG is commonly used to the maximum Scavenging activity assessing liver, for the ICG PDR after obstructive jaundice rats partially hepatectomized testing result as shown in Figure 4 (wherein K value represent ICG the clearance rate in blood plasma), the ICG PDR for the treatment of group is significantly higher than matched group (P<0.05), and this shows that hepatocellular Scavenging activity and biliary system obtain and obviously improves.
Further to the pathology of hepar for the treatment of group and control rats change carry out observations also and sham operated rats compare.Result shows that rats in sham-operated group hepatic tissue leaflet structure is clear, and liver rope is complete, does not have obvious bile duct proliferation and hepatocyte injury (Fig. 5 A).All there is hepatocyte injury to a certain degree in treatment group (Fig. 5 C) and matched group (Fig. 5 B), but the hepatocyte quantity of the swelling for the treatment of group and vacuolar degeneration is obviously less than matched group.
Test according to method identical above, wherein only the dosage of neostigmine is changed respectively into 500 μ g/kg, 32 μ g/kg.Result all shows, and Anisodamine and neostigmine use in conjunction have significantly promotion liver regeneration effect, alleviate the hepatocyte quantity of swelling and vacuolar degeneration in lobules of liver, promote the recovery of liver function.
As can be seen here, Anisodamine and neostigmine use in conjunction can promote the liver regeneration of hepatectomy rat, significantly improve the hepatocyte division and proliferation of the remaining liver of obstructive jaundice Hepatectomy, thus effectively can prevent and treat the generation of Hepatectomy microhepatia syndrome and liver failure.
Anisodamine and neostigmine use in conjunction can promote the functional rehabilitation of liver after obstructive jaundice hepatectomy, the ICG plasma clearance showing as medication therapy groups is significantly higher than saline control group, and serum albumin levels is also significantly higher than saline control group.Therefore Anisodamine and neostigmine use in conjunction can promote the recovery of Hepatectomy patient liver function.
Anisodamine and neostigmine use in conjunction can alleviate the hepatocellular degree of injury of obstructive jaundice Hepatectomy, alleviate the hepatocyte quantity of swelling and vacuolar degeneration in lobules of liver.
These are only the specific embodiment of the present invention; but protection scope of the present invention is not limited thereto; on the basis of the technical scheme that those skilled in the art discloses in the present invention, the change that can easily expect or replacement, be all interpreted as dropping within protection scope of the present invention.
Claims (9)
1. cholinesterase inhibitor and muscarinic acceptor blocker combine the purposes for the preparation of promoting in the medicine of liver regeneration.
2. purposes according to claim 1, wherein cholinesterase inhibitor and muscarinic acceptor blocker combine the purposes for the preparation of promoting at Hepatectomy in the medicine of liver regeneration.
3. purposes according to claim 1, wherein cholinesterase inhibitor and muscarinic acceptor blocker combine the purposes in the medicine of the hepatic insufficiency caused because of hepatocyte lazy weight for the preparation for the treatment of or prevention.
4. purposes according to claim 3, wherein cholinesterase inhibitor and muscarinic acceptor blocker combine the purposes in the medicine of the hepatic insufficiency caused because of hepatocyte lazy weight for the preparation for the treatment of or prevention Hepatectomy.
5. purposes according to claim 1, wherein cholinesterase inhibitor and muscarinic acceptor blocker combine the medicine for the preparation of prevention or treatment microhepatia syndrome.
6. purposes according to claim 5, wherein cholinesterase inhibitor and muscarinic acceptor blocker combine the medicine for the preparation of prevention or treatment Hepatectomy microhepatia syndrome.
7., according to the purposes of any one of claim 1 ~ 6, wherein said cholinesterase inhibitor is neostigmine.
8. the purposes according to any one of claim 1 ~ 7, wherein said muscarinic acceptor blocker is Anisodamine.
9. the purposes according to any one of claim 1 ~ 8, wherein the part by weight of cholinesterase inhibitor and muscarinic acceptor blocker is 1:50-800, is preferably 1:200-600, is more preferably 1:500.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105943537A (en) * | 2016-06-28 | 2016-09-21 | 顾万清 | Compound anisodamine and neostigmine sustained-release tablet and preparation method thereof |
Citations (2)
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| CN102580099A (en) * | 2011-10-20 | 2012-07-18 | 中国人民解放军第二军医大学 | Composition for resisting ischemia reperfusion injury and preparation method and application thereof |
| US20120322719A1 (en) * | 2011-06-16 | 2012-12-20 | The Feinstein Institute For Medical Research | Methods of treatment of fatty liver disease by pharmacological activation of cholinergic pathways |
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20120322719A1 (en) * | 2011-06-16 | 2012-12-20 | The Feinstein Institute For Medical Research | Methods of treatment of fatty liver disease by pharmacological activation of cholinergic pathways |
| CN102580099A (en) * | 2011-10-20 | 2012-07-18 | 中国人民解放军第二军医大学 | Composition for resisting ischemia reperfusion injury and preparation method and application thereof |
Non-Patent Citations (1)
| Title |
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| 黎国器: "《重症肝炎与肝硬化防治的问答》", 30 November 2003, 第二军医大学出版社 * |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105943537A (en) * | 2016-06-28 | 2016-09-21 | 顾万清 | Compound anisodamine and neostigmine sustained-release tablet and preparation method thereof |
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Effective date of registration: 20230224 Address after: No. 188, Meishan Meiliang Road, Binhu District, Wuxi City, Jiangsu Province, 214000 Patentee after: Wuxi round road medical science and Technology Research Institute Co.,Ltd. Address before: Editorial Department of Chinese Journal of Hepatobiliary Surgery, No. 28, Fuxing Road, Haidian District, Beijing, 100853 Patentee before: Gu Wanqing |